Epithelial tumors, especially those originating in the respiratory tract, are among the major causes of death due to cancer. Although chemotherapeutic agents are able to reduce tumors in a high proportion of patients with small cell carcinoma of the lung (SCCL) and squamous carcinomas of the head and neck (SqCHN), drug resistance develops rapidly. We have recently studied the development of resistance to methotrexate (MTX), cis-platinum (CDDP), L-phenylalanine mustard (L-PAM), and 4-hydroperoxy cyclophosphamide (4-HC) in human SqCHN and SCCL cell lines. At levels of resistance which are relevant to the clinic, decreased plasma membrane drug transport was observed in the resistant sublines compared to the parent cell lines. Along with decrease in drug transport, we have observed reduced 48 kD glycoprotein in the surface membrane of SqCHN cells resistant to MTX and CDDP. The CDDP-resistent SqCHN lines was cross resistant to L-PAM. We also found reduction in a plasma membrane glycolipid in SCCL cells resistant to CDDP, L-PAM and 4-HC. We have developed monoclonal antibodies to these membrane components. We now plan to determine the presence of these newly-described membrane components in cells which have reverted to drug sensitivity, compared with the drug- resistant and parent cells. We will isolate, purify and determine the structure of these membrane antigens. Clinical specimens from patients with known treatment and response histories will be examined for their content of these antigens. These studies can provide important information on the basic mechanisms of resistance to chemotherapeutic agents.